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Quantitative Structure-Permeation Relationships (QSPeRs) to Predict Skin Permeation: A Critical Evaluation

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Abstract

Purpose. Development of reliable mathematical models to predict skin permeability remains a challenging objective. This article examines some of the existing algorithms and critically evaluates their statistical relevance.

Methods. Complete statistics were recalculated for a number of published models using a stepwise multiple regression procedure. The predictivity of the models was obtained by cross-validation using a “leave-one-out” deletion pattern. The relative contribution of each independent variable to the models was calculated by a standardization procedure.

Results. The heterogeneity of the data in terms of skin origin and experimental conditions has been shown to contribute to the residual variance in existing models. Furthermore, rigorous statistics demonstrate that some published models are based on nonsignificant parameters. As such, they afford misleading mechanistic insight and will lead to over-interpretation of the data.

Conclusions. The large number of published models reflects the need for predictive tools in cutaneous drug delivery and toxicology. However, such models are more reliable when confined within well-defined chemical classes, and their applicability is often limited by the narrow property space of the set of permeants under study.

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REFERENCES

  1. D. Howes, R. H. Guy, J. Hadgraft, J. Heylings, U. Hoeck, F. Kemper, H. I. Maibach, J. P. Marty, H. Merk, J. Parra, D. Rekkas, I. Rondelli, H. Schaefer, U. Täuber, and N. Verbiese. Methods for assessing percutaneous absorption. ATLA 24:81-106 (1996).

    Google Scholar 

  2. E. L. Cussler. Diffusion: Mass Transfer in Fluid Systems, 2nd ed. Cambridge University Press, New York, 1997.

    Google Scholar 

  3. J. C. Shah. Analysis of permeation data: evaluation of the lag time method. Int. J. Pharm. 90:161-169 (1993).

    Google Scholar 

  4. B. W. Barry. Dermatological Formulations. Dekker, New York, 1983.

    Google Scholar 

  5. S. Wold. Validation of QSAR's. Quant. Struct. Act. Relat. 10:191-193 (1991).

    Google Scholar 

  6. H. Kubinyi. QSAR and 3D QSAR in drug design. Part 1: methodology. Drug Discovery Today 2:457-467 (1997).

    Google Scholar 

  7. A. Golbraikh and A. Tropsha. Beware of q2! J. Mol. Graphics Model. 20:269-276 (2002).

    Google Scholar 

  8. H. Mager and A. Barth. Problems involved in the specification and interpretation of quantitative structure-activity relationships. Pharmazie 34:557-559 (1979).

    Google Scholar 

  9. P. P. Mager. Non-least-squares regression analysis applied to organic and medicinal chemistry. Med. Res. Rev. 14:553-588 (1994).

    Google Scholar 

  10. A. L. Bunge and R. L. Cleek. A new method for estimating dermal absorption from chemical exposure. 2. Effect of molecular weight and octanol-water partitioning. Pharm. Res. 12:88-95 (1995).

    Google Scholar 

  11. T. X. Xiang and B. D. Anderson. The relationshipo between permeant size and permeability in lipid bilayer membranes. J. Membrane Biol. 140:111-122 (1994).

    Google Scholar 

  12. A. N. Martin. Physical Pharmacy. Physical Chemical Principle in the Pharmaceutical Sciences. Les & Febiger, Philadelphia, 1993.

    Google Scholar 

  13. G. B. Kasting, R. L. Smith, and E. R. Cooper. Effect of lipid solubilities and molecular size on percutaneous absorption. In B. Shroot and H. Schaefer (eds.), Skin Pharmacokinetics. Karger, Basel, 1987, pp. 138-153.

    Google Scholar 

  14. N. El Tayar, R. S. Tsai, B. Testa, P. A. Carrupt, C. Hansch, and A. Leo. Percutaneous penetration of drugs: a quantitative structure-permeability relationship study. J. Pharm. Sci. 80:744-749 (1991).

    Google Scholar 

  15. M. S. Roberts, W. J. Pugh, and J. Hadgraft. Epidermal permeability: penetrant structure relationships. 2. The effect of H-bonding groups in penetrants on their diffusion through the stratum corneum. Int. J. Pharm. 132:23-32 (1996).

    Google Scholar 

  16. M. J. Kamlet and R. W. Taft. The solvatochromic comparison method. I. The β-scale of solvent hydrogen-bond acceptor (HBA) basicities. J. Am. Chem. Soc. 98:377-383 (1976).

    Google Scholar 

  17. R. W. Taft and M. J. Kamlet. The solvatochromic comparison method. 2. The α-scale of solvent hydrogen-bond donor (HBD) acidities. J. Am. Chem. Soc. 98:2886-2894 (1976).

    Google Scholar 

  18. D. E. Leahy. Intrinsic molecular volume as a measure of the cavity term in linear solvation energy relationships: octanol-water partition coefficients and aqueous solubilities. J. Pharm. Sci. 75:629-636 (1986).

    Google Scholar 

  19. M. H. Abraham and H. S. Chadha. Application of a solvation equation to drug transport properties. In V. Pliska, B. Testa, and H. van de Waterbeemd (eds.), Lipophilicity in Drug Action and Toxicology. VCH Publishers, Weinheim, 1996, pp. 311-337.

    Google Scholar 

  20. M. H. Abraham. Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes. Chem. Soc. Rev. 22:73-83 (1993).

    Google Scholar 

  21. A. Pagliara, G. Caron, G. Lisa, W. Fan, P. Gaillard, P. A. Carrupt, B. Testa, and M. H. Abraham. Solvatochromic analysis of di-n-butyl ether/water partition coefficients as compared to other solvent systems. J. Chem. Soc. Perkin Trans. 2:2639-2643 (1997).

    Google Scholar 

  22. G. Steyaert, G. Lisa, P. Gaillard, G. Boss, F. Reymond, H. H. Girault, P. A. Carrupt, and B. Testa. Intermolecular forces expressed in 1,2-dichloroethane/water partition coefficient: a solvatochromic analysis. J. Chem. Soc. Faraday Trans. 93:401-406 (1997).

    Google Scholar 

  23. A. Pagliara, E. Khamis, A. Trinh, P. A. Carrupt, R. S. Tsai, and B. Testa. Structural properties governing retention mechanisms on RP-HPLC stationary phase used for lipophilicity measurements. J. Liquid Chromatogr. 18:1721-1745 (1995).

    Google Scholar 

  24. M. H. Abraham, H. S. Chadha, and R. C. Mitchell. Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain. J. Pharm. Sci. 83:1257-1268 (1994).

    Google Scholar 

  25. G. R. Famini and L. Y. Wilson. Using theoretical descriptors in quantitative structure activity relationships and linear free energy relationships. Network Science Co., 1116 Miller Mountain Road, Saluda, NC 28773. www.netsci.org/Science/Compchem/feature08.html (1996).

  26. J. S. Murray, P. Politzer, and G. R. Famini. Theoretical alternatives to linear solvation energy relationships. J. Mol. Struct. 454:299-306 (1998).

    Google Scholar 

  27. C. Hansch and A. Leo. Substituent Constants for Correlation Analysis in Chemistry and Biology. John Wiley & Sons, New York, 1979.

    Google Scholar 

  28. W. T. Nauta and R. F. Rekker (eds.), The Hydrophobic Fragmental Constant. Elsevier, Amsterdam, 1977.

    Google Scholar 

  29. B. Testa, L. B. Kier, and P. A. Carrupt. A systems approach to molecular structure, intermolecular recognition, and emergence-dissolvence in medicinal research. Med. Res. Rev. 17:303-327 (1997).

    Google Scholar 

  30. B. Testa, P. A. Carrupt, P. Gaillard, F. Billois, and P. Weber. Lipophilicity in molecular modeling. Pharm. Res. 13:335-343 (1996).

    Google Scholar 

  31. V. Pliska, B. Testa, and H. van de Waterbeemd (eds.). Lipophilicity in Drug Action and Toxicology. VCH, Weinheim, 1996.

    Google Scholar 

  32. B. Testa, H. van de Waterbeemd, G. Folkers, and R. H. Guy (eds.). Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Strategies. Wiley-VHCA, Zurich, 2001.

    Google Scholar 

  33. N. El Tayar, B. Testa, and P. A. Carrupt. Polar intermolecular interactions encoded in partition coefficients: an indirect estimation of hydrogen-bond parameters of polyfunctional solutes. J. Phys. Chem. 96:1455-1459 (1992).

    Google Scholar 

  34. G. Caron, F. Reymond, P. A. Carrupt, H. H. Girault, and B. Testa. Combined molecular lipophilicity descriptors and their role in understanding intramolecular effects. Pharm. Sci. Technol. Today 2:327-335 (1999).

    Google Scholar 

  35. R. C. Young, R. C. Mitchell, T. H. Brown, C. R. Ganellin, R. Griffiths, M. Jones, K. K. Rana, D. Saunders, I. R. Smith, N. E. Sore, and T. J. Wilks. Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J. Med. Chem. 31:656-671 (1988).

    Google Scholar 

  36. C. R. Ganellin, A. Fkyerat, S. K. Hosseini, Y. S. Khalaf, A. Piripitsi, W. Tertiuk, J. M. Arrang, M. Garbarg, X. Ligneau, and J. C. Schwartz. Structure-activity studies with histamine H3-receptor ligands. J. Pharm. Belg. 50:179-187 (1995).

    Google Scholar 

  37. C. R. Ganellin, A. Fkyerat, B. Bang-Andersen, S. Athmani, W. Tertiuk, M. Garbarg, X. Ligneau, and J. C. Schwartz. A novel series of (phenoxyalkyl)imidazoles as potent H3-receptor histamine antagonists. J. Med. Chem. 39:3806-3813 (1996).

    Google Scholar 

  38. B. Testa, P. A. Carrupt, P. Gaillard, and R. S. Tsai. Intramolecular interactions encoded in lipophilicity: their nature and significance. In V. Pliska, B. Testa, and H. van de Waterbeemd (eds.), Lipophilicity in Drug Action and Toxicology. VCH Publishers, Weinheim, 1996, pp. 49-71.

    Google Scholar 

  39. M. S. Roberts, R. A. Anderson, and J. Swarbrick. Permeability of human epidermis to phenolic compounds. J. Pharm. Pharmacol. 29:677-683 (1977).

    Google Scholar 

  40. R. J. Scheuplein and I. H. Blank. Permeability of the skin. Pharmacol. Rev. 51:702-747 (1971).

    Google Scholar 

  41. J. Houk and R. H. Guy. Membrane models for skin penetration studies. Chem. Rev. 88:455-471 (1988).

    Google Scholar 

  42. G. Ridout, J. Houk, R. H. Guy, G. C. Santus, J. Hadgraft, and L. L. Hall. An evaluation of structure-penetration relationships in percutaneous absorption. Farmaco 47:869-892 (1992).

    Google Scholar 

  43. R. H. Guy and J. Hadgraft. Structrure-activity correlations in percutaneous absorption. In R. L. Bronaugh and H. I. Maibach (eds.), Percutaneous Absorption. Mechanisms-Methodology-Drug Delivery. Marcel Dekker, New York, 1989, pp. 95-109.

    Google Scholar 

  44. G. L. Flynn. Physicochemical determinants of skin absorption. In T. R. Gerrity and C. J. Henry (eds.), Principles of Route-to-Route Extrapolation for Risk Assessment. Elsevier, Amsterdam, 1990, pp. 93-127.

    Google Scholar 

  45. R. O. Potts and R. H. Guy. Predicting skin permeability. Pharm. Res. 9:663-669 (1992).

    Google Scholar 

  46. D. Southwell, B. W. Barry, and R. Woodford. Variations in permeability of human skin within and between specimens. Int. J. Pharm. 18:299-309 (1984).

    Google Scholar 

  47. A. Wilshut, W. F. ten Berge, P. J. Robinson, and T. E. McKone. Estimating skin permeation. The validation of five mathematical skin permeation models. Chemosphere 30:1275-1296 (1995).

    Google Scholar 

  48. R. H. Guy and R. O. Potts. Penetration of industrial chemicals across the skin: a predictive model. Am. J. Ind. Med. 23:711-719 (1993).

    Google Scholar 

  49. T. E. McKone and R. A. Howd. Estimating dermal uptake of nonionic organic chemicals from water and soil. I. Unified fugacity-based models for risk assessments. Risk Anal. 12:543-557 (1992).

    Google Scholar 

  50. S. L. Brown and J. E. Rossi. A simple method for estimating dermal absorption of chemicals in water. Chemosphere 19:1989-2001 (1989).

    Google Scholar 

  51. V. Fiserova-Bergerova, J. T. Pierce, and P. O. Droz. Dermal absorption potential of industrial chemicals: criteria for skin notation. Am. J. Ind. Med. 17:617-635 (1990).

    Google Scholar 

  52. P. S. Magee. Some novel approaches to modelling transdermal penetration and reactivity with epidermal proteins. In J. Devillers (ed.), Comparative QSAR. Taylor & Francis, London, 1998, pp. 137-168.

    Google Scholar 

  53. L. A. Kirchner, R. P. Moody, E. Doyle, R. Bose, J. Jeffery, and I. Chu. The prediction of skin permeability by using physicochemical data. ATLA 25:359-370 (1997).

    Google Scholar 

  54. M. T. D. Cronin, J. C. Dearden, G. P. Moss, and G. Murray-Dickson. Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships. Eur. J. Pharm. Sci. 7:325-330 (1999).

    Google Scholar 

  55. H. F. Frasch and D. P. Landsittel. Regarding the sources of data analyzed with quantitative structure-skin permeability relationship methods (commentary on “Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships”). Eur. J. Med. Chem. 15:399-403 (2002).

    Google Scholar 

  56. R. O. Potts and R. H. Guy. A predictive algorithm for skin permeability: the effects of molecular size and hydrogen bond activity. Pharm. Res. 12:1628-1633 (1995).

    Google Scholar 

  57. M. H. Abraham, H. S. Chadha, and R. C. Mitchell. The factors that influence skin penetration of solutes. J. Pharm. Pharmacol. 47:8-16 (1995).

    Google Scholar 

  58. M. H. Abraham and J. C. McGowan. The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography. Chromatographia 23:243-246 (1987).

    Google Scholar 

  59. M. H. Abraham, F. Martins, and R. C. Mitchell. Algorithms for skin permeability using hydrogen bond descriptors: the problem of steroids. J. Pharm. Pharmacol. 49:858-865 (1997).

    Google Scholar 

  60. M. H. Abraham, H. S. Chadha, F. Martins, R. C. Mitchell, M. W. Bradbury, and J. A. Gratton. Hydrogen bonding part. 46. A review of the correlation and prediction of transport properties by an LFER method: physicochemical properties, brain penetration and skin permeability. Pestic. Sci. 55:75-88 (1999).

    Google Scholar 

  61. S. Rey. Hydrogen-bonds and Other Recognition Forces in Molecular Modeling. Ph.D. Thesis, University of Lausanne (2002).

  62. W. J. Pugh, M. S. Roberts, and J. Hadgraft. Epidermal permeability-penetrant structure relationships. 3. The effect of hydrogen bonding interactions and molecular size on diffusion across the stratum corneum. Int. J. Pharm. 138:149-165 (1996).

    Google Scholar 

  63. W. J. Pugh and J. Hadgraft. Ab initio prediction of human skin permeability coefficients. Int. J. Pharm. 103:163-178 (1994).

    Google Scholar 

  64. E. J. Lien and H. Gao. QSAR analysis of skin permeability of various drugs in man as compared to in vitro and in vitro studies in rodents. Pharm. Res. 12:583-587 (1995).

    Google Scholar 

  65. W. J. Pugh, I. T. Degim, and J. Hadgraft. Epidermal permeability-penetrant structure relationships. 4. QSAR of permeant diffucion across human stratum corneum in terms of molecular weight, H-bonding and electronic charge. Int. J. Pharm. 197:203-211 (2000).

    Google Scholar 

  66. M. D. Barratt, Quantitative structure-activity relationships for skin permeability. Toxicol. in Vitro 9:27-37 (1995).

    Google Scholar 

  67. J. C. Dearden, M. T. D. Cronin, H. Patel, and O. A. Raevsky. QSAR prediction of human skin permeability coefficients. J. Pharm. Pharmacol. 52(Suppl):221(2000).

    Google Scholar 

  68. D. F. Veber, S. R. Johnson, H. Y. Cheng, B. R. Smith, K. W. Ward, and K. D. Kopple. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45:2615-2623 (2002).

    Google Scholar 

  69. T. Ghafourian and S. Fooladi. The effect of structural QSAR parameters on skin penetration. Int. J. Pharm. 217:1-11 (2001).

    Google Scholar 

  70. P. Buchwald and N. Bodor. A simple, predictive, structure-based skin permeability model. J. Pharm. Pharmacol. 53:1087-1098 (2001).

    Google Scholar 

  71. J. E. Johnson, D. Blankstein, and R. Langer. Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. J. Pharm. Sci. 86:1162-1172 (1997).

    Google Scholar 

  72. J. J. Hostynek and P. S. Magee. Modelling in vivo human skin absorption. Quant. Struct. Act. Relat. 16:473-479 (1997).

    Google Scholar 

  73. M. E. Johnson, D. Blankschtein, and R. Langer. Permeation of steroids through human skin. J. Pharm. Sci. 84:1144-1146 (1995).

    Google Scholar 

  74. I. T. Degim, W. J. Pugh, and J. Hadgraft. Skin permeability data: anomalous results. Int. J. Pharm. 170:129-133 (1998).

    Google Scholar 

  75. R. J. Scheuplein, I. H. Blank, G. J. Baruner, and D. J. MacFarlane. Percutaneous absorption of steroids. J. Invest. Dermatol. 52:63-70 (1969).

    Google Scholar 

  76. B. E. Vecchia and A. Bunge. Evaluating the transdermal permeability of chemicals. In R. H. Guy and J. Hadgraft (eds.), Transdermal Drug Delivery. Marcel Dekker, New York, 2003, pp. 25-55.

    Google Scholar 

  77. B. E. Vecchia and A. Bunge. Skin absorption databases and predictive equations. In R. H. Guy and J. Hadgraft (eds.), Transdermal Drug Delivery. Marcel Dekker, New York, 2003, pp. 57-141.

    Google Scholar 

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Authors and Affiliations

  1. Institute of Medicinal Chemistry, BEP, University of Lausanne, CH-1015, Lausanne, Switzerland

    Sandrine Geinoz, Bernard Testa & Pierre-Alain Carrupt

  2. Centre Interuniversitaire de Recherche et d'Enseignement, Universities of Geneva and Lyon, “Pharmapeptides,”, F-74166, Archamps, France

    Richard H. Guy

  3. School of Pharmacy, University of Geneva, CH-1211, Geneva 4, Switzerland

    Richard H. Guy

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  1. Sandrine Geinoz
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Geinoz, S., Guy, R.H., Testa, B. et al. Quantitative Structure-Permeation Relationships (QSPeRs) to Predict Skin Permeation: A Critical Evaluation. Pharm Res 21, 83–92 (2004). https://doi.org/10.1023/B:PHAM.0000012155.27488.2b

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